1. Field of the Invention
The present invention relates to novel transient prodrug forms of pilocarpine useful in the treatment of glaucoma, to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
For purposes of this specification, the term "prodrug" denotes a derivative of pilocarpic acid which derivative, when administered topically to the eye of warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. pilocarpine, in the ocular tissue thereof.
The term "transient" indicates that the conversion of the prodrug forms proceeds in such a manner that the proven drug form (parent pilocarpine) is released, and the moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
These novel prodrug forms of pilocarpine are certain pilocarpic acid derivatives which possess a disirable high lipophilicity in comparison to the parent compound, pilocarpine.
2. Description of the Prior Art
A pharmaceutical and medical need exists for new and useful compounds indicated for the management of glaucoma in warm-blooded animals. This need exists because the compound of choice, pilocarpine, exhibits an extremely low ocular bioavailability per se and from pharmaceutical dosage forms; only 1-3% or less of an instilled pilocarpine dose gain access to the internal eye structure (cf., e.g. Lee & Robinson (1979) and references cited therein). This poor ability of pilocarpine to penetrate across the cornea is generally attributed to the low lipophilicity of the drug pilocarpine. Because of the low bioavailability, massive ophthalmic dosing is required in order to enable an antiglaucoma effective amount of pilocarpine to reach the interior of the eye, (cf. Lerman & Reininger (1971). This massive dosing and low ocular bioavailability give rise to concern about systemic toxicity since most of the applied pilocarpine is then available for systemic absorption from the nasolacrimal duct (cf. Patton & Francoeur (1978)). The systemic absorption of pilocarpine may lead to undesired side-effects, e.g. in those patients who display sensitivity to cholinergic agents.
Another serious problem associated with pilocarpine is its short duration of action. Upon instillation into the eye, the duration of lowering of the intraocular pressure caused by pilocarpine lasts only for about 3 h. As a consequence thereof, the frequency of administration is at an inconvenient 3 to 8 times per day. Patient compliance with such treatment regimens is poor, and failure to comply is likely to contribute to inadequate pressure control and deterioration of vision (cf. Norell (1980); Norell & Granstrom (1980)).
Furthermore, the frequent administration of massive amounts of pilocarpine is associated with transient peaks of high drug concentration in the eye which in turn result in undesirable side-effects such as induced myopia and miosis. Since these side-effects are dose-related, the development of means to achieve a low-level, prolonged-effect therapy would represent a major advantage (cf. Lerman & Reininger (1971); Shell & Baker (1974)).
In view of the foregoing, it is quite obvious that a serious need exists for improved forms of pilocarpine which will overcome the aforementioned disadvantages. From the foregoing, it also appears that successful pilocarpine forms should exhibit a high lipophilicity in order to enable an efficient penetration through the corneal membrane, should be converted to the active pilocarpine once the corneal barrier has been passed, and finally should lead to a controlled release and prolonged duration of action of pilocarpine.